PROJECT SUMMARY Crohn's Disease (CD), a chronic inflammatory bowel condition, affects over 1 million Americans and costs billions of dollars annually. Frequent and accurate evaluation of bowel inflammation and fibrosis is critical to guide therapy. Ultrasound is safe, cost-effective, and widely available, thus provides an attractive alternative to contrast enhanced CT/MRI for frequent follow-ups. Here we propose a multi-parameter ultrasound imaging approach combining B-mode, VesselQuest (a new microvessel imaging method with much higher sensitivity than conventional Doppler), and Comb-push Ultrasound Shearwave Elastography (CUSE) for comprehensive evaluation of CD inflammation and fibrosis burden. Specific Aim 1: Technical Advancement. Synthetic Transmit Aperture imaging with coded virtual sources will be used to improve the resolution and penetration of the high definition version VesselQuestHD. Random Singular Value Decomposition (SVD) and randomized spatial down-sampling will be used to accelerate SVD for realtime VesselQuestRT imaging. We will improve CUSE with marching push beams for shear wave generation, and harmonic imaging for shear wave detection. Pilot patient tests will be conducted to optimize these technologies and pave the way for clinical studies below. Specific Aim 2: Comparison with MRI. We will study 100 CD patients to investigate efficacy of this new technology for disease evaluation and treatment outcome prediction. Patients starting a new medical therapy will have contrast enhanced MRI (used as reference standard) at baseline and 6-months post therapy, and ultrasound at baseline, 4-weeks, and 6-months. The correlation of ultrasound parameters with MRI scores at baseline and 6-months will be assessed. The efficacy of ultrasound for differentiating mild vs. severe disease will be assessed by ROC (Receiver Operating Characteristic) analysis. In addition, ROC analysis will be used to assess whether ultrasound parameters at baseline or 4-weeks can predict treatment response at 6-months. Specific Aim 3: Reproducibility Study. Two sonographers will repeatedly scan 45 CD patients. Intraclass correlation coefficients will be used to evaluate the inter-sonographer agreement for ultrasound parameters. The within patient variance component from the model will provide an estimate of the inter-sonographer variance, which represents a lower bound for the minimum detectable difference for longitudinal follow-ups. Specific Aim 4: Comparison with Surgical Pathology. We will study 50 CD patients to investigate the efficacy of this new technology for evaluating fibrosis, using surgical pathology as the reference standard. The association of ultrasound parameters with fibrosis category obtained from pathology will be assessed using Spearman rank correlation. In addition, ROC analysis will be used to assess whether individual or combined ultrasound parameters can distinguish between none-to-moderate versus severe fibrosis. Successful completion of this project will lead to a novel technology for frequent follow-ups of Crohn's disease.